Chemogenetic manipulation of ventral pallidal neurons impairs acquisition of sign‐tracking in rats

Abstract

Cues associated with rewarding events acquire value themselves as a result of the incentive value of the reward being transferred to the cue. Consequently, presentation of a reward-paired cue can trigger reward-seeking behaviors towards the cue itself (i.e., sign-tracking). The ventral pallidum (VP) has been demonstrated to be involved in a number of motivated behaviors, both conditioned and unconditioned. However, its contribution to the acquisition of incentive value is unknown. Using a discriminative autoshaping procedure with levers, we investigated the effects of disrupting VP activity in rats on the emergence of sign-tracking using chemogenetics (Designer Receptors Exclusively Activated by Designer Drugs; DREADDs). Transient disruption of VP neurons (activation of the inhibitory hM4D(Gi) DREADD through systemic injections of clozapine N-oxide (CNO) prior to each autoshaping session) impaired acquisition of sign-tracking (lever press rate) without having any effect on approach to the site of reward delivery (i.e., goal-tracking) nor on the expression of sign-tracking after it was acquired. In addition, we conducted electrophysiological recordings in freely behaving rats following VP DREADD activation. The majority of VP units that were responsive to CNO injections exhibited rapid inhibition relative to baseline, a subset of CNO-responsive units showed delayed excitation, and a smaller subset displayed a mixed response of inhibition and excitation following CNO injections. We argue that disruption of VP during autoshaping specifically disrupted the transfer of incentive value that was attributed to the lever cue, suggesting a surprisingly fundamental role for the VP in acquiring compared to expressing Pavlovian incentive values.

Retrosplenial cortex is required for the retrieval of remote memory for auditory cues

“…Another explanation involves differences in the methods used to manipulate RSC in the two experiments (i.e., permanent electrolytic or neurotoxic lesions in Experiment 1, chemogenetics in Experiment 2). Specifically, in our laboratory, we have found that DREADD expression is not evident in all cells in the target region, and not all infected cells are inhibited by CNO (Chang et al 2015). Thus, the DREADD manipulation in Experiment 2 may be tantamount to a "partial lesion" of the RSC, which may leave context fear memory intact.…”

“…This viral vector contained a gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) (Armbruster et al 2007;Urban and Roth 2014) that suppresses neural activity when activated by systemic injection of clozapine-n-oxide (CNO; e.g., Robinson et al 2014;Chang et al 2015). Control rats were infused with a viral vector (AAV-hSyn-GFP) that did not contain the hM4Di receptor (n ¼ 8; Group GFP).…”

DREADDS: Use and application in behavioral neuroscience.

“…For instance, a current question in the field of reward learning is how complex Pavlovian motivational behaviors (e.g., sign-tracking) are acquired over weeks. To address that, KSS has used DREADDs to transiently inactivate target brain areas each day during a two-week acquisition period (Chang, Todd, Bucci, & Smith, 2015). In our and others' experiences, CNO has been repeatedly used in the same animals to acutely activate DREADDs (with CNO doses up to 20 mg/kg by SVM) repeatedly, without evidence of decaying effects, hangover-like effects, or lingering behavioral issues that may confound subsequent behavior(Mahler, Vazey, & Aston-Jones, 2013; Mahler et al, 2014; S. Robinson et al, 2014).…”

“…KSS and DJB have found a similar circa 60% suppression of activity in awake-behaving animals expressing hM4Di in the same pallidal structure upon i.p. CNO administration (Chang, Todd, Bucci, et al, 2015). In that work, an average onset latency of the change in firing was 12 minutes after CNO delivery and response offset (i.e., return to baseline) occurred at ca.…”

“…As a final example, we (KSS, DJB) have used the hM4Di DREADD to examine the involvement of the ventral pallidum in motivational attraction to reward cues (Chang, Todd, Bucci, et al, 2015). Animals often approach and attempt to consume discrete cues paired with rewards, such as insertion of a lever, in a behavior called sign-tracking.…”